In the last year, we demonstrated that there were at least two distinct subpopulations of helper T cells that initiate the generation of allospecific CTL responses, including (1) L3T4+Lyt2- Th that is class II MHC-restricted, and (2) L3T4-Lyt2+ Th that is class I MHC-restricted, and (2) L3T4-Lyt2+ Th that is class I MHC-restricted. The recognition repertoire of Lyt2+ Th was very narrow in that Lyt2+ Th cells were activated exclusively by class I alloantigens. In contrast, the recognition repertoire of L3T4+ Th was broad in that L3T4+ Th cells responded to class I alloantigens, class II (self or allo) antigens, as well as minor-H and TNP-modified self MHC antigens. Precursor frequency of Lyt2+ Th cells was found to be similar to that of L3T4+ Th cells, suggesting the biological significance of this novel Th subset. In fact, it was demonstrated that Lyt2+ subset played an essential role in the rejection of allo-class I disparate skin grafts in vivo. Finally, it was indicated that functionally distinct but phenotypically identical Lyt2+ Th and Lyt2+ CTL differed in their differentiation pathway, even though they are both class I-specific, and this might explain the difference between their fine recognition specificities defined by mutant class I stimulators.